Even with impressive advances in medical care witnessed over the past century, infectious diseases remain the second leading cause of death worldwide accounting for 26% of all deaths. In addition, there are ever increasing public health concerns associated with the threat of bioterrorism. Because of the low immunogenicity, poor public perception, and often painful side-effects associated with the currently used anthrax vaccine, there is need to develop novel adjuvants that will allow for single dose administration and induction of protective immunity against the anthrax toxin. The overall objectives of this R03 application are to demonstrate the immune enhancing capabilities of polymer adjuvants based on novel biodegradable polyanhydride chemistries to modulate the induction and activation of host immune responses against the recombinant protective antigen (rPA) of Bacillus anthracis. The specific aims of this project are: 1) to demonstrate the structural and antigenic stability of rPA following encapsulation into polyanhydride nanoparticles;2) to demonstrate the ability of novel polymer adjuvants to induce enhanced immune responses against the rPA of Bacillus anthracis. Single-dose vaccines are cost-effective, eliminate the need for multiple injections, and result in greater patient compliance (i.e., no need for a return visit). Development and application of this adjuvant technology will facilitate the rational design of vaccines and the ability to appropriately redirect the immune response to develop protective immunity. The insights obtained during the performance of these studies will provide the basis for designing immunomodulatory polymer adjuvants that will impact the development of safe, stable, single-dose, non-toxic vaccines that may provide long term protection against other common diseases (e.g., diphtheria, tetanus, polio). All together, this integrated approach brings together expertise in polymer chemistry, immunology, and bacterial pathogenesis that will provide novel insights into the activity of polymer adjuvants as it relates to the relationships between adjuvant chemistry and induction of protective immunity. PUBLIC HEALTH RELEVANCE: There is general need for identifying new adjuvants for use in human medicine especially adjuvants that would allow for the use of single dose vaccines leading to greater patient compliance. This project addresses the efficacy of novel polyanhydride adjuvants to induce protective immunity against anthrax using a second generation vaccine candidate, recombinant protective antigen (rPA). Because stability of the recombinant proteins is critical with respect to storage, the chemical characteristics and adjuvanticity of the polymer microparticles will significantly improve the immunogenic potential of rPA.